The complement cascade has a well studied purpose and effect, including its role in desirable immunological response. However, the undesirable initiation of the complement cascade has been implicated in certain well known disorders characterized by inflammation and tissue damage. Thus, complement cascade inhibitors have been developed that can be used to treat such disorders, including hereditary angioedema, septic shock, post pump syndrome in cardiopulmonary bypass, paroxysmal nocturnal hemoglobinurea, organ rejection, wounds, brain trauma, asthma, Hashimoto's thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, multiple sclerosis, the neuropathies Guillain-Barre syndrome, Miller-Fisher syndrome, and Alzheimer's disease. See, e.g., U.S. Pat. Nos. 6,492,403 and 6,515,002.
The undesirable initiation of the complement cascade has been implicated in complications associated with cell transplantations and grafts as well. It is known that cell transplantations and grafts are desirable for treating diseases such as heart failure, diabetes, stroke, Parkinson's disease, Alzheimer's disease, dementia, liver disease, kidney disease, bums, and wounds. However, this treatment has often not been efficacious in practice due to the immunogenic nature of the cell transplantations and grafts, leading to activation of the complement cascade and eventually, to rejection. Thus, complement cascade inhibitors are desirable for ameliorating rejection.
However, it is always desirable to impart improved pharmacokinetic properties to compounds that are used to treat patients. Covalent attachment of polyethylene glycols (PEG) to protein drugs have been used to increase the in vivo circulatory time, water solubility and to decrease antigenicity of these drugs. See, for example, U.S. Pat. No. 5,711,944. It is possible to conjugate several polymer molecules to a large protein, such as, for example, insulin and hemoglobin, without interfering with the active residues that interact with its biological target. Retaining activity following conjugation of small proteins and peptides to a polymer has been more difficult because these bioactive materials often have few attachment sites not associated with biological activity. Polymer conjugation to non-peptidic small molecule drugs has been primarily limited to prodrug strategies. See, for example, U.S. Pat. No. 5,614,549, U.S. Pat. No. 5,622,986 and U.S. Pat. No. 6,127,355. In these approaches, a small molecule is linked to a non-antigenic polymer via a metabolically-labile covalent moiety, such as an ester. The drug must be released from the non-antigenic polymer by enzymatic hydrolysis of the ester to enable the small molecules to be transported across cell membranes into the cells.
Because complement cascade inhibitors bind with receptors on cell surfaces it is not necessary for them to cross cell membranes. Thus, small molecule prodrug approaches using metabolically-labile covalent linkages would be unnecessarily limiting. However, as in the case of protein drugs and small molecule prodrugs, it is nonetheless equally important to have techniques to modulate the pharmacokinetic properties of small molecule complement cascade inhibitors that do not cross cell membranes. Accordingly, there is an unfulfilled need for means to modulate the pharmacokinetic properties of small molecule complement cascade inhibitors.
The present invention is directed to these, as well as other important ends.